The present invention relates to novel dressings containing polysulfated oligosaccharides having sustained release of the said active ingredients. It also relates to a method for the preparation thereof, this method comprising a treatment step with ethylene oxide. It further relates to the uses thereof for wound care and the treatment and/or prevention of scars and stretch marks.
Oligosaccharides are carbohydrates the hydrolysis of which solely affords oses. These are sugars formed by the joining of at least two molecules of simple sugars (or oses). Oligosaccharides include sucrose also called saccharose, a double sugar formed by the condensing of 2 oses: one molecule of glucose and one molecule of fructose.
Various sulfated oligosaccharide compounds are known in the literature and have multiple biological, cosmetic and/or therapeutic activities. These compounds particularly include different salts of sucrose octasulfate such as the potassium salt of sucrose octasulfate, the sodium salt of sucrose octasulfate, the hydroxyaluminium complex of sucrose octasulfate or the amino acid salts of sucrose octasulfate. These latter compounds are known for their beneficial action in particular on problems of gastric inflammation but also on the healing.
The healing of a wound is a natural biological phenomenon, human and animal tissues being capable of repairing localised lesions via repair and regeneration processes particular thereto. The natural healing of a wound chiefly occurs in 3 successive phases each having its own cellular and molecular activity. These are successively:
The inflammatory phase which begins consecutively to trauma by the implementation of inflammatory and vascular phenomena in operation such as the forming of a blood clot composed inter alia of fibrin mediated by different cellular and molecular factors and forming a provisional matrix called “fibrinous” tissue or “yellow” tissue.
The granulation phase which is characterized by the onset at the wound site of fibroblasts and new endothelial cells needed for neovascularisation of the injured tissue. Once activated, the fibroblasts are transformed to myofibroblasts and thereby take part in the maturation of the granulation tissue.
The epithelialisation phase which is characterized by the reorganisation of the extra-cellular matrix. For example, the type-3 collagen is replaced by type-1 collagen. The proliferation of most cells is observed. These ones exhibit invasive behaviour in a first time of myofibroblast, fibroblast and endothelial cell type, and then show a substantial decrease in their activity. This phase over the longer term leads to a remodelled scar that is softened and no longer painful when the wound healing process follows a normal course. However, at this step pathological scars may occur due to poor realization of terminal healing steps.
Several general issues related to the healing process or to scars have already been the subject of research, in particular by the Applicant. One of the first problems encountered was the elimination of necrotic and/or fibrinous tissue during the inflammatory phase. Indeed, if the process of natural debridement is insufficient, whereby this tissue is eliminated, this is to the detriment of the healing process. Numerous solutions have been put forward in the past such as assisted debridement of mechanical, surgical, enzymatic, autolytic or biological type. They all have the objective of ridding wounds of their constituent fibrinous and necrotic tissue.
However these different techniques have numerous disadvantages. They prove to be too painful for the patient or too inefficient. These problems were solved through the action of compounds described in application FR 2 956 322 by Laboratoires URGO. This document describes the use of a compound selected from among polysulfated oligosaccharides having 1 to 4 ose units, the salts or complexes thereof, as wound debridement agent.
Among these compounds, the potassium salt of sucrose octasulfate was previously known for the treatment of wounds during the budding phase through its action on the fibroblasts. This action is described for example in patent applications EP 230 023, WO 89/05645 or WO 98/22114. This compound was used after performing assisted debridement of the wound and hence after removing necrotic and/or fibrinous tissue. It was therefore used on a clean, debrided wound.
The beneficial action on healing of some compounds in the family of polysulfated oligosaccharides has also been described. For example, applications FR 2 824 474 and FR 2 953 522 describe compositions containing sucralfate alone or associated with salts of transition metals for their use in the healing, the regeneration or to solve skin inflammation problems.
A further problem it was sought to solve concerned pathological scars and striae distensae (stretch marks). By pathological scars is meant atrophic, retractile or hypertrophic scars.
Stretch marks occur subsequent to rapid sudden stretching of the skin. Said stretching may result from weight gain and/or hormonal change. Each stretch mark looks like a skin tear. It is in fact dermal tissue deteriorated by a transformation phenomenon of fibroblasts to myofibroblasts. Striae distensae form parallel, elongate skin striations of several centimetres long and up to 1 centimetre in width. The stretch marks may be thin and scarcely apparent but they may have small depressions imparting an irregular aspect to the skin. At a first phase, they initially vary from pale pink to purple red (immature or inflammatory stretch marks). Over time, they tend to change colour and take on a pearly white appearance (mature stretch marks). The stretch marks then become less visible, but the scar remains. Hormonal changes associated with weight gain lead to the onset of stretch marks in numerous women during pregnancy. Genetic factors also have an influence on their onset. They may also appear in parallel with some physiological or pathological conditions and may form a symptom indicative of a genetic disease. The chief triggering factors are inflammation, mechanical stress and hormonal environment. All these factors cause stretching, disorientation and disorganisation of the collagen and elastin fibres without rupture of the supporting tissue. Stretch marks can be likened to scars (since they have undergone the same formation steps as those following after trauma to the skin). Healing thereof is currently impossible but attenuation and improvement of the lesions are possible. Curative treatments are essentially local: topical treatment with derivatives of retinoic acid or fruit acids, use of peeling or laser. However, the treatments known to date are not fully satisfactory since they are not always well tolerated and their efficacy is not fully satisfactory. There is a demand for the development of a product allowing the efficient prevention and/or treatment of stretch marks, with acceptable cutaneous tolerance.
Dressings are known, in particular from application FR 2 956 322, comprising a compound selected from the group formed of polysulfated oligosaccharides having 1 to 4 oses, the salts or derivatives thereof, preferably comprised in the coating or impregnating mass of the dressing, in order to guarantee efficient bioavailability of the active ingredient at the patient's scar site. These dressings guarantee sustained bioavailability of the active ingredient to prevent or treat problems of debridement, healing, stretch marks or pathological scars. However, it was found that after an application time of a few hours, the release of active ingredient becomes insufficient. In addition, only part of the active ingredient contained in the dressing is released onto the skin to be treated. And after an application time of a few hours a new dressing has to be applied if it is desired to maintain on the skin a sufficient level of active ingredient to reach expected efficacy. Apart from the resulting cost, regular change of dressing is not always compatible with the activities of users/patients. To obtain better treatment efficacy, it has been sought to develop dressings having much higher sustained bioavailability of active ingredient. In other words, dressings have been developed having an efficient high concentration of active ingredient at the site of injury, this efficacy being sustained in time. This result is the consequence of high, sustained release of active ingredient contained in the dressing. These new dressings therefore allow faster, more efficient patient treatment.
Additionally, a method is known in the prior art for the sterilisation of dressings via treatment with ethylene oxide. However, this type of treatment has never been applied up until now to dressings containing polysulfated oligosaccharides. In addition, it is neither mentioned nor suggested in the prior art that said treatment could lengthen the release time of an active ingredient and increase the total amount of released active ingredient, much on the contrary. It is disclosed in the prior art that all sterilisation methods (e.g. radiation sterilisation, autoclave sterilisation or even sterilisation using ethylene oxide) in theory have an unfavourable impact on the release of active ingredient contained in a dressing subject of such treatment, either because the type of sterilisation degrades the active ingredient itself or because it modifies the rheological and/or structural properties of the micro-adhering elastomeric mass in which or on which the active ingredient(s) are incorporated (Radiation effects on polypropylene/polybutylene blends, Richard J. Rolando, June 1993 Tappi Journal, Vol. 76, N°6 and Influence of processing conditions on medical material degradation/failure, Michael T. K. Ling et al., Antec 200 pages 2724 to 2730).